tbuckley/cabot-search huggingface dataset:
Enhanced neutralization of SARS-CoV-2 variant BA.2.86 and XBB sub-lineages by a tetravalent COVID-19 vaccine booster
Authors: Xun Wang, Shujun Jiang, Wentai Ma, Xiangnan Li, Kaifeng Wei, Faren Xie, Chaoyue Zhao, Xiaoyu Zhao, Shidi Wang, Chen Li, Rui Qiao, Yuchen Cui, Yanjia Chen, Jiayan Li, Guonan Cai, Changyi Liu, Jizhen Yu, Jixi Li, Zixin Hu, Wenhong Zhang, Shibo Jiang, Mingkun Li, Yanliang Zhang, Pengfei Wang
Journal: Cell Host & Microbe (2023)
Engineering irradiated tumor-derived microparticles as personalized vaccines to enhance anti-tumor immunity
Authors: Yajie Sun, Yu Tian, Shuhui Wu, Ai Huang, Yan Hu, Zhiyun Liao, Michelle Swift, Suke Deng, Xiao Yang, Bin Zhang, Zhanjie Zhang, Bian Wu, Jing Huang, Ke Jiang, Fang Huang, Honglin Jin, Chao Wan, Kunyu Yang
Journal: Cell Reports Medicine (2023)

<h2>Summary</h2> The inadequate activation of antigen-presenting cells, the entanglement of T cells, and the highly immunosuppressive conditions in the tumor microenvironment (TME) are important factors that limit the effectiveness of cancer vaccines. Studies show that a personalized and broad antigen repertoire fully activates anti-tumor immunity and that inhibiting the function of transforming growth factor (TGF)-β facilitates T cell migration. In our study, we introduce a vaccine strategy by engineering irradiated tumor cell-derived microparticles (RT-MPs), which have both personalized and broad antigen repertoire, to induce comprehensive anti-tumor effects. Encouraged by the proinflammatory effects of the spike protein from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the high affinity between TGF-β receptor 2 (TGFBR2) and TGF-β, we develop RT-MPs with the SARS-CoV-2 spike protein and TGFBR2. This spike protein and high TGFBR2 expression induce the innate immune response and ameliorate the immunosuppressive TME, thereby promoting T cell activation and infiltration and ultimately inhibiting tumor growth. Our study provides a strategy for producing an effective personalized anti-tumor vaccine.
MDSCs-derived GPR84 induces CD8<sup>+</sup>T-cell senescence via p53 activation to suppress the antitumor response
Authors: Jinyan Liu, Jiayin Liu, Guohui Qin, Jiahui Li, Ziyi Fu, Jieyao Li, Miaomiao Li, Caijuan Guo, Ming Zhao, Zhen Zhang, Feng Li, Xuan Zhao, Liping Wang, Yi Zhang
Journal: Journal for ImmunoTherapy of Cancer (2023)

Backgrounds G-protein-coupled receptor 84 (GPR84) marks a subset of myeloid-derived suppressor cells (MDSCs) with stronger immunosuppression in the tumor microenvironment. Yet, how GPR84 endowed the stronger inhibition of MDSCs to CD8 + T cells function is not well established. In this study, we aimed to identify the underlying mechanism behind the immunosuppression of CD8 + T cells by GPR84 + MDSCs. Methods The role and underlying mechanism that MDSCs or exosomes (Exo) regulates the function of CD8 + T cells were investigated using immunofluorescence, fluorescence activating cell sorter (FACS), quantitative real-time PCR, western blot, ELISA, Confocal, RNA-sequencing (RNA-seq), etc. In vivo efficacy and mechanistic studies were conducted with wild type, GPR84 and p53 knockout C57/BL6 mice. Results Here, we showed that the transfer of GPR84 from MDSCs to CD8 + T cells via the Exo attenuated the antitumor response. This inhibitory effect was also observed in GPR84-overexpressed CD8 + T cells, whereas depleting GPR84 elevated CD8 + T cells proliferation and function in vitro and in vivo. RNA-seq analysis of CD8 + T cells demonstrated the activation of the p53 signaling pathway in CD8 + T cells treated with GPR84 + MDSCs culture medium. While knockout p53 did not induce senescence in CD8 + T cells treated with GPR84 + MDSCs. The per cent of GPR84 + CD8 + T cells work as a negative indicator for patients’ prognosis and response to chemotherapy. Conclusions These data demonstrated that the transfer of GPR84 from MDSCs to CD8 + T cells induces T-cell senescence via the p53 signaling pathway, which could explain the strong immunosuppression of GPR84 endowed to MDSCs.
High-dimensional single-cell proteomics analysis of esophageal squamous cell carcinoma reveals dynamic alterations of the tumor immune microenvironment after neoadjuvant therapy
Authors: Dingpei Han, Yichao Han, Wei Guo, Wei Wei, Su Yang, Jie Xiang, Jiaming Che, Lianggang Zhu, Junbiao Hang, Tom van den Ende, Hanneke W M van Laarhoven, Bin Li, Youqiong Ye, Hecheng Li
Journal: Journal for ImmunoTherapy of Cancer (2023)

Dynamic alterations of the tumor immune microenvironment in esophageal squamous cell carcinoma (ESCC) after different neoadjuvant therapies were understudied. We used mass cytometry with a 42-antibody panel for 6 adjacent normal esophageal mucosa and 26 tumor samples (treatment-naïve, n=12; postneoadjuvant, n=14) from patients with ESCC. Single-cell RNA sequencing of previous studies and bulk RNA sequencing from The Cancer Genome Atlas were analyzed, flow cytometry, immunohistochemistry, and immunofluorescence analyses were performed. Poor tumor regression was observed in the neoadjuvant chemotherapy group. Radiotherapy-based regimens enhanced CD8+ T cells but diminished regulatory T cells and promoted the ratio of effector memory to central memory T cells. Immune checkpoint blockade augmented NK cell activation and cytotoxicity by increasing the frequency of CD16+ NK cells. We discovered a novel CCR4+CCR6+ macrophage subset that correlated with the enrichment of corresponding chemokines (CCL3/CCL5/CCL17/CCL20/CCL22). We established a CCR4/CCR6 chemokine-based model that stratified ESCC patients with differential overall survival and responsiveness to neoadjuvant chemoradiotherapy combined with immunotherapy, which was validated in two independent cohorts of esophageal cancer with neoadjuvant treatment. This work reveals that neoadjuvant therapy significantly regulates the cellular composition of the tumor immune microenvironment in ESCC and proposes a potential model of CCR4/CCR6 system to predict the benefits from neoadjuvant chemoradiotherapy combined with immunotherapy.
Randomized, open-label, phase II, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with locally advanced, inflammatory, or early HER2-positive breast cancer—Immun-HER trial (GOIRC-01-2016)
Authors: Benedetta Pellegrino, Chiara Tommasi, Olga Serra, Stefania Gori, Elisabetta Cretella, Massimo Ambroggi, Antonio Frassoldati, Giancarlo Bisagni, Chiara Casarini, Emilio Bria, Luisa Carbognin, Elena Fiorio, Antonella Mura, Claudio Zamagni, Lorenzo Gianni, Alberto Zambelli, Filippo Montemurro, Michele Tognetto, Renata Todeschini, Gabriele Missale, Nicoletta Campanini, Enrico Maria Silini, Giuseppe Maglietta, Antonino Musolino
Journal: Journal for ImmunoTherapy of Cancer (2023)

It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab. In this multicenter randomized phase II trial, all enrolled patients (pts) with T2-T4d HER2-positive BC received 3 cycles of neoadjuvant treatment (NAT) with fluorouracil, epirubicin and cyclophosphamide every 3 weeks (q21), followed by docetaxel/pertuzumab plus intravenous trastuzumab (arm A) or, docetaxel/pertuzumab plus subcutaneous (SC) trastuzumab (arm B) q21x4 cycles. After surgical operation, each pt was treated with trastuzumab q21x14 cycles using the same SC or intravenous formulation of NAT. Primary endpoint was the proportion of subjects with high stromal tumor-infiltrating lymphocytes (sTILs) in postneoadjuvant residual disease (RD). Sixty-three pts (31 (arm A) and 32 (arm B)) were enrolled. Pathological complete response was obtained by 20/31 pts (64.5%; 95% CI 45.4% to 80.1%) in arm A and 19/32 pts (59.4%; 95% CI 40.1% to 76.3%) in arm B. High sTILs were observed in 27% and 46% of postneoadjuvant residual tumors in arms A and B, respectively. CD8+ T cells increased significantly in RDs of both arms (p=0.014 and 0.002 for arm A and B, respectively), whereas a significant decline in the level of CD4+ FoxP3+ regulatory T cells was observed only in arm B (p=0.016). A significant upregulation of PD-1 on sTILs was found in RD of pts enrolled in arm B (p=0.012), while programmed death-ligand 1 (PD-L1) was significantly overexpressed in residual tumors of arm A (p=0.02). A strong negative correlation was reported in arm B between expression of PD-L1 on pretreatment sTILs and CD3 expression on sTILs in RD (τ: -0.73). Grade≥3 AE incidence rates were similar between the two arms. SC trastuzumab induced relevant sTILs enrichment, with favorable variations of immune parameters in HER2-positive BC pts with RD after NAT. Novel immunotherapy strategies should be tested to achieve SC-specific, antitumor immune response. NCT03144947, and EudraCT number: 2016-000435-41.
Improved assessment of donor liver steatosis using Banff consensus recommendations and deep learning algorithms
Authors: Alessandro Gambella, Massimo Salvi, Luca Molinaro, Damiano Patrono, Paola Cassoni, Mauro Papotti, Renato Romagnoli, Filippo Molinari
Journal: Journal of Hepatology (2023)

Background & AimsThe Banff Liver Working Group recently published consensus recommendations for steatosis assessment in donor liver biopsy, but few studies reported their use and no automated deep-learning algorithms based on the proposed criteria have been developed so far. We evaluated Banff recommendations on a large monocentric series of donor liver needle biopsies by comparing the pathologists score with that of a convolutional neural networks (CNN) we specifically developed for automated steatosis assessment.MethodsWe retrospectively retrieved 292 allograft liver needle biopsies collected between January 2016 and January 2020 and performed steatosis assessment using a former intra-institution method (pre-Banff method) and the newly introduced Banff recommendations. Scores provided by pathologists and CNN models were then compared, and the degree of agreement was measured with the Intraclass Correlation Coefficient (ICC).ResultsRegarding the pre-Banff method, a poor agreement was observed between pathologist and CNN model for small droplet macrovesicular steatosis (ICC:0.38), large droplet macrovesicular steatosis (ICC:0.08), and the final combined score (ICC:0.16) evaluation, but none of these reached statistically significance. Interestingly, significant improved agreement was observed using the Banff approach: ICC was 0.93 for the low-power score (p<0.001), 0.89 for the high-power score (p<0.001), and 0.93 for the final score (p<0.001). Comparing the pre-Banff method with the Banff approach on the same biopsy, pathologist and CNN model assessment showed a mean (±SD) percentage of discrepancy of 26.89 (± 22.16) and 1.20 (± 5.58), respectively.ConclusionsOur findings support the use of Banff recommendations in daily practice and highlight the need for a granular analysis of their effect on liver transplantation outcomes.Impact and implications• We developed and validated the first automated deep-learning algorithms for steatosis standardized assessment based on the Banff Liver Working Group consensus recommendations.• Our algorithm provides an unbiased automated evaluation of steatosis, which will lay the groundwork for granular analysis of steatosis's short- and long-term effects on organ viability to identify clinically relevant steatosis cut-off for donor organ acceptance.• Implementing our algorithm in daily clinical practice will allow a more efficient and safe allocation of donor organs, aiming at improving the post-transplant outcomes of patients.
A Single NIR‐II Laser‐Triggered Self‐Enhancing Photo/Enzyme‐coupled Three‐in‐One Nanosystems for Breast Cancer Phototheranostics
Authors: Rong Dai, Qi Liu, Binyue Zhang, Xin Zhang, Mengting Gao, Dongsheng Li, Weiwei Kang, Lin Chen, Mingxin Zhao, Ziliang Zheng, Ruiping Zhang
Journal: Advanced Healthcare Materials (2023)

Multifunctional phototheranostics, employing precise and non-invasive techniques, is widely developed to enhance theranostic efficiency of breast cancer (BC), reduce side-effects, and improve quality of life. Integrating all phototheranostic modalities into a single photosensitizer for highly effective BC treatment is particularly challenging due to the potential inefficiency and time consumption associated with repeated switching of multiple-wavelength lasers. Herein, a novel single NIR-II laser-triggered three-in-one nanosystem(PdCu NY) is rationally designed, which enables dual-modal (NIR-II FL/NIR-II PA) imaging-guided self-enhancing photothermal-photodynamic therapy (PTT-PDT) in NIR-II window. The PdCu NY based on optimal Pd/Cu molar-ratio(1:11) can be easily fabricated and large-scale production for simultaneous PTT-PDT against BC under a single 1064nm laser irradiation. Significantly, the PdCu NY acted as a promising photocatalyst for decomposition of H
Correction: Endoscopic removal of lumen-apposing metal stents – risk factors for stent embedment, complex removals, and adverse events: analysis from a multicenter prospective case series
Authors: Sergio Bazaga, Francisco Javier García-Alonso, Jose Ramon Aparicio Tormo, Belen Martinez Moreno, Vicente Sanchiz, Carles Suria, Albert Garcia-Sumalla, Joan B. Gornals, Carlos Chavarría, Carme Loras, Francisco Jose García-Fernandez, Álvaro Terán, Enrique Vazquez-Sequeiros, Rafael Pedraza Sanz, Leticia Pérez-Carazo, José Carlos Súbtil, Antonio Pérez-Millan, Francisco Uceda Porta, Victoria Busto Bea, Carlos de la Serna-Higuera, Isabel Pinto Garcia, Juan Colán-Hernández, Carlos Huertas, Carlos Guarner-Argente, Manuel Perez-Miranda
Journal: Endoscopy (2023)

Correction to: Endoscopic removal of lumen-apposing metal stents – risk factors for stent embedment, complex removals, and adverse events: analysis from a multicenter prospective case seriesEndoscopy 2023; 55(07): 591-598DOI: 10.1055/a-2030-4158
Correction: Differences in treatment of stage I colorectal cancers: a population-based study of colorectal cancers detected within and outside of a screening program
Authors: Esther Toes-Zoutendijk, Emilie C. H. Breekveldt, Lisa van der Schee, Iris D. Nagtegaal, Marloes A. G. Elferink, Iris Lansdorp-Vogelaar, Leon M. G. Moons, Monique E. van Leerdam
Journal: Endoscopy (2023)

Correction to: Differences in treatment of stage I colorectal cancers: a population-based study of colorectal cancers detected within and outside of a screening programEndoscopy eFirstDOI: 10.1055/a-2173-5989
Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease
Authors: Gizem Terzioglu, Tracy L. Young-Pearse
Journal: Molecular Neurodegeneration (2023)

Abstract Recent genetic studies on Alzheimer’s disease (AD) have brought microglia under the spotlight, as loci associated with AD risk are enriched in genes expressed in microglia. Several of these genes have been recognized for their central roles in microglial functions. Increasing evidence suggests that SHIP1, the protein encoded by the AD-associated gene INPP5D , is an important regulator of microglial phagocytosis and immune response. A recent study from our group identified SHIP1 as a negative regulator of the NLRP3 inflammasome in human iPSC-derived microglial cells (iMGs). In addition, we found evidence for a connection between SHIP1 activity and inflammasome activation in the AD brain. The NLRP3 inflammasome is a multiprotein complex that induces the secretion of pro-inflammatory cytokines as part of innate immune responses against pathogens and endogenous damage signals. Previously published studies have suggested that the NLRP3 inflammasome is activated in AD and contributes to AD-related pathology. Here, we provide an overview of the current understanding of the microglial NLRP3 inflammasome in the context of AD-related inflammation. We then review the known intracellular functions of SHIP1, including its role in phosphoinositide signaling, interactions with microglial phagocytic receptors such as TREM2 and evidence for its intersection with NLRP3 inflammasome signaling. Through rigorous examination of the intricate connections between microglial signaling pathways across several experimental systems and postmortem analyses, the field will be better equipped to tailor newly emerging therapeutic strategies targeting microglia in neurodegenerative diseases.
Walking speed and the risk of type 2 diabetes: a systematic review and meta-analysis
Authors: Ahmad Jayedi, Mahdieh-Sadat Zargar, Alireza Emadi, Dagfinn Aune
Journal: British Journal of Sports Medicine (2023)

Objective To investigate the association between walking speed and the risk of type 2 diabetes. Design Systematic review and meta-analysis. Data sources PubMed, Scopus, CENTRAL and Web of Science to 30 May 2023. Eligibility criteria for selecting studies We included cohort studies that explored the association between walking speed and the risk of type 2 diabetes in adults. We used random-effects meta-analyses to calculate relative risk (RR) and risk difference (RD). We rated the credibility of subgroup differences and the certainty of evidence using the Instrument to assess the Credibility of Effect Modification ANalyses (ICEMAN) and Grading of Recommendations Assessment, Development and Evaluation (GRADE) tools, respectively. Results Ten cohort studies were included. Compared with easy/casual walking (&lt;3.2 km/hour), the RR of type 2 diabetes was 0.85 (95% CI 0.70 to 1.00); RD=0.86 (95% CI 1.72 to 0) fewer cases per 100 patients; n=4, GRADE=low) for average/normal walking (3.2–4.8 km/hour), 0.76 (95% CI 0.65 to 0.87); RD=1.38 (95% CI 2.01 to 0.75) fewer cases per 100 patients; n=10, GRADE=low) for fairly brisk walking (4.8–6.4 km/hour) and 0.61 (95% CI 0.49 to 0.73; RD=2.24 (95% CI 2.93 to 1.55) fewer cases per 100 patients; n=6, GRADE=moderate) for brisk/striding walking (&gt;6.4 km/hour). There was no significant or credible difference across subgroups based on adjustment for the total volume of physical activity and time spent walking per day. Dose–response analysis suggested that the risk of type 2 diabetes decreased significantly at a walking speed of 4 km/h and above. Conclusions Low to moderate certainty evidence, mainly from studies with a high risk of bias, suggests that walking at faster speeds is associated with a graded decrease in the risk of type 2 diabetes. PROSPERO registration number CRD42023432795.
Evaluating the epidemiology of clozapine-associated neutropenia among people on clozapine across Australia and Aotearoa New Zealand: a retrospective cohort study
Authors: Korinne Northwood, Nicholas Myles, Scott R Clark, Susanna Every-Palmer, Hannah Myles, Steve Kisely, Nicola Warren, Dan Siskind
Journal: The Lancet Psychiatry (2023)
The effect of expectancy versus actual gluten intake on gastrointestinal and extra-intestinal symptoms in non-coeliac gluten sensitivity: a randomised, double-blind, placebo-controlled, international, multicentre study
Authors: Marlijne C G de Graaf, Clare L Lawton, Fiona Croden, Agnieszka Smolinska, Bjorn Winkens, Martine A M Hesselink, Gonny van Rooy, Peter L Weegels, Peter R Shewry, Peter D Mooney, Lesley A Houghton, Ben J M Witteman, Daniel Keszthelyi, Fred J P H Brouns, Louise Dye, Daisy M A E Jonkers
Journal: The Lancet. Gastroenterology & hepatology (2023)
Ageism: the -ism affecting the lives of older people living with HIV
Authors: Giovanni Guaraldi, Jovana Milic, Mario Cascio, Cristina Mussini, Esteban Martinez, Jules Levin, Daniele Calzavara, Rebecca Mbewe, Julian Falutz, Chloe Orkin, Matteo Cesari, Jeffrey V Lazarus
Journal: The Lancet HIV (2023)
A novel quantitative urine LAM antigen strip for point-of-care tuberculosis diagnosis in non-HIV adults
Authors: Zhen Huang, Huan Huang, Jing Hu, Lu Xia, Xuhui Liu, Rong Qu, Xiaolin Huang, Yang Yang, Kang Wu, Ruiqing Ma, Jinchuan Xu, Zhenyan Chen, Yuhao Wu, Juan Yang, Yong Fang, Jianfeng Zeng, Weihua Lai, Guodong Sui, Wei Sha, Yonghua Xiong, Shuihua Lu, Xiao-Yong Fan
Journal: Journal of Infection (2023)
Engineered mesenchymal stem cell-derived small extracellular vesicles for diabetic retinopathy therapy through HIF-1α/EZH2/PGC-1α pathway
Authors: Fengtian Sun, Yuntong Sun, Xiaoling Wang, Junyan Zhu, Shenyuan Chen, Yifan Yu, Mengyao Zhu, Wenrong Xu, Hui Qian
Journal: Bioactive Materials (2023)

Diabetic retinopathy (DR) is a leading cause of blindness worldwide with limited treatment options. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) hold promise as a cell-free therapy for retinal diseases. In this study, we present evidence that the intravitreal injection of MSC-sEVs improved retinal function and alleviated retinal apoptosis, inflammation, and angiogenesis in both db/db mice and streptozotocin-induced diabetic rats. Mechanistically, hyperglycemia-induced activation of hypoxia-inducible factor-1α (HIF-1α) inhibited the tripartite motif 21 (TRIM21)-mediated ubiquitination and degradation of enhancer of zeste homologue 2 (EZH2), ultimately resulting in the downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) through EZH2-induced methylation modification. The presence of miR-5068 and miR-10228 in MSC-sEVs targeted the HIF-1α/EZH2/PGC-1α pathway. The blockade of miR-5068 and miR-10228 abolished the retinal therapeutic effects of MSC-sEVs. Additionally, we engineered MSC-sEVs with elevated levels of miR-5068 and miR-10228 to enhance retinal repair efficiency. Together, our findings provide novel insights into the mechanism underlying DR progress and highlight the potential of MSC-sEVs, especially engineered MSC-sEVs, as a therapeutic option for DR.
Revolutionizing sphincter preservation in ultra-low rectal cancer: exploring the potential of transanal endoscopic intersphincteric resection (taE-ISR): a propensity score-matched cohort study
Authors: Ximo Xu, Hao Zhong, Jun You, Mingyang Ren, Abe Fingerhut, Minhua Zheng, Jianwen Li, Xiao Yang, Haiqin Song, Sen Zhang, Chengsheng Ding, Naijipu Abuduaini, Mengqin Yu, Jingyi Liu, Yi Zhang, Liang Kang, Zhenghao Cai, Bo Feng
Journal: International Journal of Surgery (2023)

Background: With the optimization of neoadjuvant treatment regimens, the indications for intersphincteric resection (ISR) have expanded. However, limitations such as unclear surgical field, impaired anal function, and failure of anal preservation still exist. Transanal total mesorectal excision can complement the drawbacks of ISR. Therefore, this study combined these two techniques and proposed transanal endoscopic intersphincteric resection (taE-ISR), aiming to explore the value of this novel technique in anal preservation for ultra-low rectal cancer. Material and methods: Four high-volume centres were involved. After 1:1 propensity score-matching, patients with ultra-low rectal cancer underwent taE-ISR ( n =90) or ISR ( n =90) were included. Baseline characteristics, perioperative outcomes, pathological results, and follow-up were compared between the two groups. A nomogram model was established to assess the potential risks of anal preservation. Results: The incidence of adjacent organ injury (0.0% vs. 5.6%, P =0.059), positive distal resection margin (1.1% vs. 8.9%, P =0.034), and incomplete specimen (2.2% vs. 13.3%, P =0.012) were lower in taE-ISR group. Moreover, the anal preservation rate was significantly higher in taE-ISR group (97.8% vs. 82.2%, P =0.001). Patients in the taE-ISR group showed a better disease-free survival ( P =0.044) and lower cumulative recurrence ( P =0.022) compared to the ISR group. Surgery procedure, tumour distance, and adjacent organ injury were factors influencing anal preservation in patients with ultra-low rectal cancer. Conclusion: taE-ISR technique was safe, feasible, and improved surgical quality, anal preservation rate and survival outcomes in ultra-low rectal cancer patients. It held significant clinical value and showed promising application prospects for anal preservation.